Genome-wide association study of breast cancer susceptibility
Although breast cancer susceptibility exhibits a strong familial pattern of inheritance, until recently the list of associated genes accounted for less than 25% of familial risk. In 2007 a genome-wide association study was conducted by Easton et al. to identify additional genes contributing to breast cancer susceptibility. (1) The study consisted of 4,398 breast cancer cases and 4,316 controls. This was followed by an analysis of 21,860 case and 22,578 controls looking at 30 identified single nucleotide polymorphisms (SNPS) from 22 studies. Five SNPs were strongly associated with breast cancer. From these, four genes with a likely causative role in breast cancer were identified, FGFR2, TNRC9, MAP3K1 AND LSP1. Background After skin cancer, breast cancer is the most common cancer in women across all ethnicities. In 2010 (the most recent data available) 206,966 women and over 2,000 men in the U.S were diagnosed with breast cancer. There were over 41,000 U.S. deaths caused by breast cancer in the same year. (2) A first- degree relative of women with breast cancer have nearly twice the life-time risk of the disease. Two important genes, BRCA1 and BRCA2 were identified in the 1990s as playing a considerable role in the inheritance of breast cancer. The relative absence of other major genes being identified since these two has lead many to look at breast cancer as a polygenic disease. Large-scale case-control studies of have identified rare mutations that confer up to a twofold risk of breast cancer. Study Design The authors conducted a three stages association study in an attempt to identify novel breast cancer associated genes. Recent sequencing advances allow for a high number of SNPs to be reviewed. In the first stage, 266,722 SNPs were chosen to identify common variants across the whole genome. 408 breast cancer cases with a strong family history, and 400 control cases in the UK were selected for sequencing of >80% of these SNPs. A strong family history was defined as at least two first-degree relatives affected. The second stage of this study selected 12,711 SNPs for having the highest statistically significance difference between the two groups. An additional 3,990 invasive breast cancer cases and 3,916 controls from the SEARCH study were sequenced for these identified SNPs of interest. Genotyping for rounds 1 and 2 were done using high-density oligonucleotide microarrays. The final stage of the study evaluated the associated risk of 30 of the most significant SNPs from 21,860 cases of invasive breast cancer, 988 cases of DCIS, and 22,578 controls across 22 case-control studies. These studies were conducted in North America, Europe, South-East Asia and Australia 3 as part of the Breast Cancer Association Consortium. Results Five novel breast cancer susceptibility loci, from four different genes, were identified as having a high significant association (p<10-7) with breast cancer incidence. FGFR2 contained the SNP (rs2981582) with the highest association. Analysis of FGFR2 and prevalence of other characterized SNPs from this gene, indicated that variation in expression of this receptor tyrosine kinase the observed association with breast cancer. 5-10% of breast tumors over express FGFR2. Two SNPs (rs12443621 and rs8051542) with evident association were mapped to the TNRC9 gene. The presence of a putative high mobility group box motif indicates that TNRC9 functions as a transcription factor. Two additional genes, MAP3K1 and LSP1, were associated with an increase risk of breast cancer-- based on the occurrence pattern of the SNPs rs889312 and rs3817198, respectively -- which demonstrated a dose dependent relationship (heterozygous vs. homozygous). References 1. Easton DF, et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087-1093. 2. Center for Disease Control Website (http://www.cdc.gov/cancer/breast/statistics/.http://www.cdc.gov/cancer/breast/statistics/.